This revised application for multicenter clinical trials of two carbonic anhydrase inhibitors in the periodic paralyses has been prepared with the help of planning grant R21 NS 39939-01A1. This grant was awarded because the carbonic anhydrase inhibitors (CAI) acetazolamide (ACZ) and dichlorphenamide (DCP) have been used in the periodic paralyses (PP) for many years but there is uncertainty whether treatment will prevent the chronic, progressive weakness that afflicts PP patients. Moreover, it is not known which agent, ACZ or DCP is preferable for attack prevention and treatment/prevention of weakness. Only 10% of patients are maintained on DCP, which may be preferred treatment. In the past decade, the molecular defects of many of the PP's have been identified, making possible the study of treatment in molecularly- defined patients with PP. We propose 14-center randomized controlled trials to test the pragmatic hypotheses that (1) DCP and ACZ will decrease the frequency of attacks of weakness in hyperkalemic PP (HYP) and in hypokalemic PP (HOP); (2) DCP will improve strength-to a greater extent than ACZ or placebo in both PP's; and (3) that DCP and ACZ will improve quality of life in both types of PP. The trials will also test the explanatory hypotheses that specific ion channel mutations will: (1) predict differing phenotypes and (2) predict differing responses to ACZ and DCP and that (3) ACZ/DCP effects on electrolyte and acid/base status are related to treatment responses. The planned HYP-HOP trials will: (1) develop standard treatments for the PP; (2) defend recommendations for long-term treatments in PP; (3) provide data for regulatory approval of DCP, which is essential to have it available for clinical use; (4) lay the groundwork for broader insight into channel dysfunction in the PP and a large number of neuromuscular and CNS channelopathies; (5) provide clinical resources for collaborating basic science laboratories to study pathomechanisms of channelopathies in vivo and vitro.